Involvement of cyclooxygenase‐2 in hyperplastic gastritis induced by <i>Helicobacter pylori</i> infection in C57BL/6 mice

Xiao, Fang; Furuta, Takahisa; Takashima, Misako; Shirai, Naohito; Hanai, Hiroyuki

doi:10.1046/j.1365-2036.2001.00965.x

Cited by 28 publications

(15 citation statements)

References 44 publications

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“…H. pylori infection is a major risk factor for gastric carcinoma. H. pylori up-regulated COX-2 mRNA expression and stimulated release of prostaglandin E 2 in a gastric cancer cell line (10), as well as in the gastric mucosa of animal models and in humans (12,14). Therefore, high levels of H. pylori infection might up-regulate COX-2 expression, which, in turn, could lead to the development of gastric carcinogenesis (27).…”

Section: Discussionmentioning

confidence: 99%

The Selective Cyclooxygenase-2 Inhibitor Nimesulide Prevents Helicobacter pylori -Associated Gastric Cancer Development in a Mouse Model

Nam

Hahm

et al. 2004

Clinical Cancer Research

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Purpose: Helicobacter pylori infection can lead to gastric cancer, and cyclooxygenase-2 (COX-2) is overexpressed in the stomach during H. pylori infection. Therefore, we investigated whether nonsteroidal anti-inflammatory drugs might protect against this form of cancer. Specifically, we examined the chemopreventive effect of the COX-2 inhibitor nimesulide on H. pylori-associated gastric carcinogenesis in mice.Experimental Design: C57BL/6 mice were treated with the carcinogen N-methyl-N-nitrosourea (MNU) and/or H. pylori. To determine the effect of COX-2 inhibition, nimesulide was mixed with feed pellets and administered for the duration of the experiment. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. In vitro experiments with the human gastric cancer cell line AGS were also performed to identify mechanisms underlying cancer chemoprevention by nimesulide.Results: Gastric tumors developed in 68.8% of mice that were given both MNU and H. pylori, whereas less than 10% developed gastric tumors when given either MNU or H. pylori alone. These findings indicate that H. pylori promotes carcinogen-induced gastric tumorigenesis. In mice treated with both MNU and H. pylori, nimesulide administration substantially reduced H. pylori-associated gastric tumorigenesis, whereas substantial inductions of apoptosis were observed. In vitro studies demonstrated that nimesulide and H. pylori when combined acted synergistically to induce more apoptosis than either alone.Conclusions: Our data show that nimesulide prevents H. pylori-associated gastric carcinogenesis, and suggest that COX-2 may be a target for chemoprevention of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

The Selective Cyclooxygenase-2 Inhibitor Nimesulide Prevents Helicobacter pylori -Associated Gastric Cancer Development in a Mouse Model

Nam

Hahm

et al. 2004

Clinical Cancer Research

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“…In the transgenic mice with a standard diet, we found that the glandular length was shortened and foveolae were deepened in the gastric corpus, while antral glands were elongated which is a common pathological change in hyperplasia. 29,30 In addition, a significant decrease of parietal cells is a key step toward gastric adenocarcinoma, which has been suggested in previous studies. 22,31 Therefore, similar structural characteristics observed in this study suggest that a synergistic effects of a high salt diet and intestinal metaplasia may facilitate the conversion of the gastric mucosa to a hyperplastic state, although the entire thickness of gastric mucosa was not increased.…”

Section: Discussionmentioning

confidence: 92%

Intestinal metaplasia with a high salt diet induces epithelial proliferation and alters cell composition in the gastric mucosa of mice

Xiao

Crissey²,

Lynch³

et al. 2005

Cancer Biology & Therapy

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Intestinal metaplasia of the gastric mucosa is an important component in the pathway to adenocarcinoma. The mechanisms that induce the progression from intestinal metaplasia to cancer have not been elucidated. High dietary salt has been known as one of the risk factors for gastric cancer development in humans. Therefore, we investigated the role of high salt diet on gastric epithelial cell proliferation and differentiation, using our mouse model that ectopically expressed Cdx2 homeodomain transcription factor and induced an intestinal metaplastic phenotype in the gastric epithelia. Sixty Cdx2 transgenic and sixty age-matched wild-type littermates were studied. Fifty-percent Cdx2 transgenic and wild type mice were administered a high-salt diet and the other fifty-percent was fed a standard diet starting at 12 weeks after birth. At 10, 20 and 40 weeks after initiation of the diets, histopathological changes were determined by Hemotoxylin and Eosin, alcian blue, and periodic acid-Schiff (PAS) staining. Cell types and cell kinetics were assessed by immunohistochemistry. At 52 weeks, significant alterations in pathology were observed in the Cdx2 transgenic mice fed a high-salt diet, including elongation of gastric pits, reduction of the glandular zone in the gastric corpus, and deepening of glands in the antrum. In the Cdx2 transgenic mice fed a high salt diet, the parietal and chief cells were significantly decreased in the gastric corpus. A significant increase in cell proliferation and apoptosis in the corpus and antrum were observed in Cdx2 transgenic mice fed a high-salt diet as compared to wild-type littermates. Taken together, these data implicate that intestinal metaplasia in concert with a high-salt diet induces epithelial proliferation, apoptosis, and alters cellular types in the gastric mucosa of mice. Alteration in the composition of the gastric epithelium may play a role in influencing the microenvironment to engender susceptibility to carcinogens.

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“…Thus it may be considered that induction of COX-2 in ACT-GAS mice is partly due to the development of hypertrophy of the gastric mucosa. Finally, the possibility of infection with Helicobacter species shouled be considered, because various reports (30,33,40) have demonstrated that H. pylori infection induces COX-2 expression in the stomach. However, Helicobacter species could not be detected in the stomachs of our ACT-GAS mice using PCR that can detect Helicobacter species (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…COX-2 is also upregulated in gastritis and gastric cancer induced by H. pylori (2,30). Interestingly, COX-2 inhibition markedly reduces gastric mucosal hypertrophy induced by H. pylori infection in C57BL/6 mice (40). COX-2 inhibition also suppressed gastric cancer induced by N-methyl-NЈ-nitro-N-nitrosoguanidine in rats (8).…”

mentioning

confidence: 97%

Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice

Kanda¹,

Seno²,

Kawada³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Gastrin promotes gastric mucosal growth, and hypergastrinemia induces gastric mucosal hypertrophy. Recently, it has been reported that gastrin induces cyclooxygenase-2 (COX-2) in human gastric and colorectal cancer cell lines. However, whether COX-2 is involved in gastrin-induced gastric mucosal growth in vivo is unknown. We investigated the role of COX-2 in gastrin-induced gastric mucosal hypertrophy using gastrin transgenic mice. Hypergastrinemic mice [mice with mutated gastrin under the control of the beta-actin promoter (ACT-GAS mice)] received the COX-2 inhibitor celecoxib (0, 200, or 500 mg/kg of diet) from 5 wk of age and were killed at 16 or 24 wk. Some ACT-GAS mice received celecoxib from 16 wk and were killed at 24 wk. Eighty-week-old ACT-GAS mice without celecoxib treatment were also examined. The thickness of the gastric mucosa, cell populations, COX-2 expression, and PGE(2) levels were evaluated. All ACT-GAS mice showed gastric mucosal hypertrophy, and four of six 80-wk-old ACT-GAS mice developed gastric cancer. COX-2 was expressed in interstitial cells of the hypertrophic gastric mucosa and gastric cancers. Moreover, PGE(2) levels in the gastric mucosa of ACT-GAS mice were significantly higher than those of normal mice. With treatment with celecoxib, PGE(2) levels, the gastric mucosal thickness, and the number of total gastric cells per gastric gland of ACT-GAS mice were significantly decreased. The decrease in gastric mucosal thickness was caused by a reduction of foveolar hyperplasia. The thickness of glandules and the number of Ki67-positive cells were not significantly changed. In conclusion, COX-2 contributes to gastrin-induced mucosal hypertrophy of the stomach.

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Involvement of cyclooxygenase‐2 in hyperplastic gastritis induced by Helicobacter pylori infection in C57BL/6 mice

Cited by 28 publications

References 44 publications

The Selective Cyclooxygenase-2 Inhibitor Nimesulide Prevents Helicobacter pylori -Associated Gastric Cancer Development in a Mouse Model

The Selective Cyclooxygenase-2 Inhibitor Nimesulide Prevents Helicobacter pylori -Associated Gastric Cancer Development in a Mouse Model

Intestinal metaplasia with a high salt diet induces epithelial proliferation and alters cell composition in the gastric mucosa of mice

Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice

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